My primary research focus is to use a powerful novel insertional mutagen, the Sleeping Beauty (SB) transposon system, to address fundamental questions in cancer genetics. My training has previously focused on developing SB for forward genetic screens for cancer genes in mice. In my own research laboratory, I would like to pursue additional experiments studying the role of genes identified by SB in the context of human cancer, initially focusing on the BRAF oncogene. In addition, I would like to adapt the SB system to elucidate the genetics of a fundamental problem in human cancer treatment, namely therapy resistance. I propose to use the SB system to identify genes that are involved in acquired resistance to BAY 43-9006, a kinase inhibitor now showing promise in clinical trials as a chemotherapeutic agent. In addition, I propose to use the SB system to identify genes involved in prostate cancer progression as a result of acquired insensitivity to hormone ablation therapies. The role of identified genes in therapy resistance will be tested in human cancer models. These projects will be initiated in my final year as a post-doctoral fellow at the University of Minnesota. The SB system was originally developed for vertebrate genetics at the University of Minnesota, and my mentor's laboratory is a member of the Arnold and Mabel Beckman Center for Transposon Research. As a member of the Cancer Center, I have access to several Core facilities that will provide support to the projects proposed here. During my final year as a post-doctoral fellow, I will apply to assistant professor positions at Universities with strong research programs. My long-term career goal is to establish a research laboratory that uses novel genetic approaches to study human cancer biology and treatment. The proposed research employs a novel technology, the Sleeping Beauty transposon system, to identify genes involved in both cancer initiation and progression to therapy resistance. This research is relevant to human health as understanding the genetics of the disease is an important step toward developing more effective, patient-specific therapies. In addition, we hypothesize that this technology will be useful for creating better models of human cancer that will be useful for drug discovery and testing.